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Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.

Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M - Br. J. Cancer (2011)

Bottom Line: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline.At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001).We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.

ABSTRACT

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.

Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.

Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.

Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

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Presence and distribution of CAR in non-transformed colon mucosa, adenomas, primary, and metastatic colon cancers. Real time RT–PCR data represent median CAR mRNA expression level of non-transformed mucosa, adenomas, primary colon cancers, and metastases displaying highest CAR expression in adenomas (A). Immunohistochemistry revealed abundant CAR presence at the plasma membrane (black bars) in non-transformed mucosa samples, adenomas, primary colon cancer, and metastases. In colon cancers, a significant decrease of membranous CAR immunoreactivity was found. Cytoplasmic CAR immunopositivity (grey bars) was observed significantly more often in adenomas, primary colon cancers, and metastases (asterisks mark significant differences compared with normal mucosa) (B). Typical results for CAR immunostaining are shown in non-transformed colon mucosa, displaying CAR localisation at the apical plasma membrane (arrow), whereas in adenomas additional cytoplasmic CAR immunoreactivity was noted (arrow). CAR immunoreactivity in primary colon cancers was preferentially seen in the cytoplasm (arrow), whereas CAR presence at plasma membrane was frequently lost. In contrast, metastases displayed both membranous and cytoplasmic CAR presence (C) (magnification: × 100, bar=200 μm).
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fig1: Presence and distribution of CAR in non-transformed colon mucosa, adenomas, primary, and metastatic colon cancers. Real time RT–PCR data represent median CAR mRNA expression level of non-transformed mucosa, adenomas, primary colon cancers, and metastases displaying highest CAR expression in adenomas (A). Immunohistochemistry revealed abundant CAR presence at the plasma membrane (black bars) in non-transformed mucosa samples, adenomas, primary colon cancer, and metastases. In colon cancers, a significant decrease of membranous CAR immunoreactivity was found. Cytoplasmic CAR immunopositivity (grey bars) was observed significantly more often in adenomas, primary colon cancers, and metastases (asterisks mark significant differences compared with normal mucosa) (B). Typical results for CAR immunostaining are shown in non-transformed colon mucosa, displaying CAR localisation at the apical plasma membrane (arrow), whereas in adenomas additional cytoplasmic CAR immunoreactivity was noted (arrow). CAR immunoreactivity in primary colon cancers was preferentially seen in the cytoplasm (arrow), whereas CAR presence at plasma membrane was frequently lost. In contrast, metastases displayed both membranous and cytoplasmic CAR presence (C) (magnification: × 100, bar=200 μm).

Mentions: We first studied the CAR mRNA expression by quantitative RT–PCR assays on randomly selected tissue specimens of normal colon mucosa (n=10), adenomas (n=14), primary colon cancers (n=15), and colon cancer metastases (n=13). These studies showed that the median ΔCT values for CAR mRNA in comparison with normal mucosa (0.8805) increased significantly in adenomas (1.621; P=0.049), whereas a decrease of CAR mRNA expression was found in primary colon cancers (0.3920; n.s.) and colon cancer metastases (0.2040; P=0.032) (Figure 1A).


Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.

Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M - Br. J. Cancer (2011)

Presence and distribution of CAR in non-transformed colon mucosa, adenomas, primary, and metastatic colon cancers. Real time RT–PCR data represent median CAR mRNA expression level of non-transformed mucosa, adenomas, primary colon cancers, and metastases displaying highest CAR expression in adenomas (A). Immunohistochemistry revealed abundant CAR presence at the plasma membrane (black bars) in non-transformed mucosa samples, adenomas, primary colon cancer, and metastases. In colon cancers, a significant decrease of membranous CAR immunoreactivity was found. Cytoplasmic CAR immunopositivity (grey bars) was observed significantly more often in adenomas, primary colon cancers, and metastases (asterisks mark significant differences compared with normal mucosa) (B). Typical results for CAR immunostaining are shown in non-transformed colon mucosa, displaying CAR localisation at the apical plasma membrane (arrow), whereas in adenomas additional cytoplasmic CAR immunoreactivity was noted (arrow). CAR immunoreactivity in primary colon cancers was preferentially seen in the cytoplasm (arrow), whereas CAR presence at plasma membrane was frequently lost. In contrast, metastases displayed both membranous and cytoplasmic CAR presence (C) (magnification: × 100, bar=200 μm).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3101933&req=5

fig1: Presence and distribution of CAR in non-transformed colon mucosa, adenomas, primary, and metastatic colon cancers. Real time RT–PCR data represent median CAR mRNA expression level of non-transformed mucosa, adenomas, primary colon cancers, and metastases displaying highest CAR expression in adenomas (A). Immunohistochemistry revealed abundant CAR presence at the plasma membrane (black bars) in non-transformed mucosa samples, adenomas, primary colon cancer, and metastases. In colon cancers, a significant decrease of membranous CAR immunoreactivity was found. Cytoplasmic CAR immunopositivity (grey bars) was observed significantly more often in adenomas, primary colon cancers, and metastases (asterisks mark significant differences compared with normal mucosa) (B). Typical results for CAR immunostaining are shown in non-transformed colon mucosa, displaying CAR localisation at the apical plasma membrane (arrow), whereas in adenomas additional cytoplasmic CAR immunoreactivity was noted (arrow). CAR immunoreactivity in primary colon cancers was preferentially seen in the cytoplasm (arrow), whereas CAR presence at plasma membrane was frequently lost. In contrast, metastases displayed both membranous and cytoplasmic CAR presence (C) (magnification: × 100, bar=200 μm).
Mentions: We first studied the CAR mRNA expression by quantitative RT–PCR assays on randomly selected tissue specimens of normal colon mucosa (n=10), adenomas (n=14), primary colon cancers (n=15), and colon cancer metastases (n=13). These studies showed that the median ΔCT values for CAR mRNA in comparison with normal mucosa (0.8805) increased significantly in adenomas (1.621; P=0.049), whereas a decrease of CAR mRNA expression was found in primary colon cancers (0.3920; n.s.) and colon cancer metastases (0.2040; P=0.032) (Figure 1A).

Bottom Line: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline.At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001).We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.

ABSTRACT

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.

Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.

Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.

Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

Show MeSH
Related in: MedlinePlus